rs1126568

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_004168.4(SDHA):​c.1799G>A​(p.Arg600Gln) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R600W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000034 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SDHA
NM_004168.4 missense

Scores

6
7
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:10B:1

Conservation

PhyloP100: 8.92

Publications

7 publications found
Variant links:
Genes affected
SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
SDHA Gene-Disease associations (from GenCC):
  • hereditary pheochromocytoma-paraganglioma
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • pheochromocytoma/paraganglioma syndrome 5
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • mitochondrial complex II deficiency, nuclear type 1
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • neurodegeneration with ataxia and late-onset optic atrophy
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • Leigh syndrome
    Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • gastrointestinal stromal tumor
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Leigh syndrome with leukodystrophy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • mitochondrial complex II deficiency
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • dilated cardiomyopathy 1GG
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_004168.4

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHANM_004168.4 linkc.1799G>A p.Arg600Gln missense_variant Exon 14 of 15 ENST00000264932.11 NP_004159.2 P31040-1A0A024QZ30

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHAENST00000264932.11 linkc.1799G>A p.Arg600Gln missense_variant Exon 14 of 15 1 NM_004168.4 ENSP00000264932.6 P31040-1
ENSG00000286001ENST00000651543.1 linkn.*532G>A non_coding_transcript_exon_variant Exon 13 of 24 ENSP00000499215.1 A0A494C1T6
ENSG00000286001ENST00000651543.1 linkn.*532G>A 3_prime_UTR_variant Exon 13 of 24 ENSP00000499215.1 A0A494C1T6

Frequencies

GnomAD3 genomes
AF:
0.0000791
AC:
12
AN:
151738
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000488
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000209
AC:
5
AN:
239052
AF XY:
0.0000155
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000112
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000186
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000345
AC:
50
AN:
1450124
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
29
AN XY:
720116
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000908
AC:
3
AN:
33046
American (AMR)
AF:
0.0000463
AC:
2
AN:
43242
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25838
East Asian (EAS)
AF:
0.0000506
AC:
2
AN:
39508
South Asian (SAS)
AF:
0.0000356
AC:
3
AN:
84326
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52706
Middle Eastern (MID)
AF:
0.000745
AC:
4
AN:
5370
European-Non Finnish (NFE)
AF:
0.0000316
AC:
35
AN:
1106154
Other (OTH)
AF:
0.0000167
AC:
1
AN:
59934
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.312
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000790
AC:
12
AN:
151856
Hom.:
0
Cov.:
30
AF XY:
0.0000808
AC XY:
6
AN XY:
74278
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000486
AC:
2
AN:
41122
American (AMR)
AF:
0.0000654
AC:
1
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5186
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000103
AC:
7
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2104
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.358
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000843
Hom.:
0
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:5
Oct 10, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The frequency of this variant in the general population, 0.00015 (3/19410 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with paragangliomas (PMIDs: 28384794 (2018) and 25595276 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dec 20, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PP3, PP4 -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 14, 2019
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27011036, 25595276, 28384794, 30877234) -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1
May 05, 2025
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R600Q variant (also known as c.1799G>A), located in coding exon 14 of the SDHA gene, results from a G to A substitution at nucleotide position 1799. The arginine at codon 600 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in individuals with features consistent with hereditary paraganglioma-pheochromocytoma (von Dobschuetz E et al. Endocr. Relat. Cancer, 2015 Apr;22:191-204; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Ben Aim L et al. J. Med. Genet., 2019 08;56:513-520; Ambry internal data). The alteration was also detected in two gastrointestinal stromal tumors (GIST), which tested negative for SDHB by immunohistochemistry (Boikos SA et al. JAMA Oncol, 2016 Jul;2:922-8), and was reported as a germline finding in two additional individuals with SDHB-deficient GISTs (Pantaleo MA et al. Front Oncol, 2021 Jan;11:778461). This alteration was also reported in conjunction with a second SDHA variant of unknown significance in a patient with respiratory chain group mitochondrial disease (Wu T et al. Pediatr Neurol, 2022 Jul;132:11-18). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Dec 30, 2022
Genetics and Molecular Pathology, SA Pathology
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dilated cardiomyopathy 1GG Uncertain:1
Jan 22, 2024
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Oct 07, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in individuals with SDHA-related conditions (PMID: 25595276, 28384794). ClinVar contains an entry for this variant (Variation ID: 259244). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with glutamine at codon 600 of the SDHA protein (p.Arg600Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Gastrointestinal stromal tumor Uncertain:1
Oct 01, 2021
“Giorgio Prodi” Cancer Research Center, University of Bologna
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Feb 13, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

SDHA-related disorder Benign:1
Jan 07, 2020
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Uncertain
0.044
T
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
T
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.43
T
M_CAP
Pathogenic
0.84
D
MetaRNN
Uncertain
0.58
D
MetaSVM
Uncertain
0.47
D
PhyloP100
8.9
PROVEAN
Benign
1.2
N
REVEL
Uncertain
0.52
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.031
D
MutPred
0.49
Gain of MoRF binding (P = 0.0269);
MVP
0.97
ClinPred
0.64
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.75
Mutation Taster
=7/93
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.24
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.24
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1126568; hg19: chr5-254512; API